Search

O objetivo neste estudo foi relatar um caso clínico relacionando o uso da termografia infravermelha (RI) associada à ozonioterapia como ferramentas complementares para diagnosticar e tratar um processo inflamatório não infeccioso no sistema locomotor de um cavalo-atleta da Amazônia. A frequência cardíaca (FC), a frequência respiratória (RR) e a temperatura retal (TR) foram medidas tanto em repouso quanto após a caminhada. A avaliação radiográfica, a dosagem completa do hemograma e da creatina fosfoquinase (CPK) foram realizadas. O exame de IR foi realizado adicionalmente e os termogramas foram analisados usando o Flir Tools. A ozonioterapia foi realizada por via intramuscular na área escapular. Todas as comparações foram realizadas utilizando ANOVA e teste de Tukey (5%). O animal apresentou FC, RR e TR, todos dentro dos limites da normalidade. Quando o animal foi levado a andar, demonstrou dor e FC (48 batimentos.min-1) e RR (60 respirações.min-1). A dosagem de creatina fosfoquinase foi de 79 UL-1 e o IR mostrou que a região torácica apresentava temperatura superficial de até 39,1ºC, indicando processo inflamatório. Após a ozonioterapia houve redução do padrão de cor branca de 39,1ºC para 37,2ºC. A termografia por infravermelho é uma técnica eficiente que pode ser usada para o diagnóstico de inflamação e a terapia com ozônio é um tratamento inovador.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy characterized by delayed, protracted vomiting and accompanied by lethargy and pallor, usually 1 to 4 hours after ingesting the food allergen. The pathophysiology of FPIES remains unknown, and currently there are no diagnostic biomarkers available to assess disease activity or its resolution. Over the last 2 decades, FPIES has become increasingly recognized in both pediatric and adult patients. Forty years after the initial FPIES description, the first FPIES code appeared in the International Classification of Diseases, Tenth Revision (ICD-10), and the first international consensus guidelines for the diagnosis and management of FPIES were published. On June 22, 2022, the National Institute of Allergy and Infectious Diseases (NIAID) held its first virtual multidisciplinary workshop on FPIES. Various clinical and translational aspects of FPIES as well as important areas of unmet needs were discussed as priorities for future research during this 2-day virtual workshop. Our report provides a summary of content of the workshop, including updated literature on the topic areas, and also provides critical commentary on the state of FPIES., Competing Interests: Disclosure statement The workshop was supported by funds from the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID). The authors of this report are responsible for its content. Statements in the report do not necessarily represent the official views of or imply endorsement by the National Institutes of Health, NIAID, the Department of Health and Human Services, or any other agency of the United States government. Disclosure of potential conflict of interest: A. Nowak-Wegrzyn reports research support from Alladapt Immunotherapeutics, DBV Technologes, Siolta Therapeutics, and Regeneron; speaking fees from Nestlé, Danone, and Thermo Fisher; consulting fees from Aquestive; royalties from UpToDate; and service as associate editor for Annals of Allergy, Asthma & Immunology, chair of the ABAI board of directors, director of the AAAAI board, and chair of the medical advisory board of the International FPIES Association. S. H. Sicherer reports royalty payments from UpToDate and from Johns Hopkins University Press; grants to his institution from the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID), Food Allergy Research and Education (FARE), and Pfizer; and personal fees from the American Academy of Allergy, Asthma & Immunology as deputy editor of the Journal of Allergy and Clinical Immunology: In Practice outside the submitted work. C. Akin reports consultancy and research support from Blueprint Medicine and Cogent for tyrosine kinase inhibitor therapies in mastocytosis outside the submitted work. S. Anvari receives funding from NIH NIAID and DBV Technologies for contracted work outside of the submitted work; and reports consultancy with DBV Technologies. L. M. Bartnikas receives research support from NIH NIAID, the International FPIES Association (IFPIES), and the Myles & Gertrude Hanson Foundation. M. C. Berin reports compensation for service on the scientific advisory board for Enterome. T. A. Bingemann reports service on the board of directors of the American Board of Allergy and Immunology and the board of regents for the American College of Allergy, Asthma and Immunology; is a member of the executive committee for AAP’s Section of Allergy and Immunology; has been a speaker for Sanofi; has been a consultant for ALK, Bryn, and Aimmune; and has served as principal investigator on a Novartis trial. G. du Toit reports grants from NIH NIAID, FARE, MRC & Asthma UK Centre, Action Medical Research, and the National Peanut Board; is scientific advisory board member for Aimmune; is investigator on pharma-sponsored peanut allergy immunotherapy studies (Aimmune, DBV Technologies, and Novartis); and is joint director of The Food Allergy Immunotherapy Centre. M. Groetch reports royalties from UpToDate, FARE, and the Academy of Nutrition and Dietetics; and serves on the medical advisory board of IFPIES, as a senior advisor to FARE, as a health sciences advisor for the American Partnership for Eosinophilic Disorders, and on the editorial board of Journal of Food Allergy. F. Schultz is employed by IFPIES; and is a consultant for Aijinomoto Cambrooke. C. Venter reports grants from Reckitt Benckiser; and personal fees from Reckitt Benckiser, Nestlé Nutrition Institute, Danone, Abbott Nutrition Else Nutrition, Sifter, Owyn, and Before Brands outside the submitted work. A. Westcott-Chavez is employed by IFPIES. R. A. Wood reports research support from Takeda Pharmaceuticals outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Post-infectious disorders of gut-brain interaction (PI-DGBI) have significant impact on children and adolescents. The effect of COVID-19 on PI-DGBI-associated symptoms in this population, however, is unknown., Methods: We performed electronic medical record searches to identify patients 8-17 years old with a SARS-CoV2 PCR test at Lurie Children's Hospital between November 2020 and March 2021 (cohort 1) and April-October 2021 (cohort 2). Questionnaires were administered to assess symptoms prior to and 3 months following the test. This included the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS), questionnaire of pediatric gastrointestinal symptoms-Rome IV, Nausea Profile (NP), dyspepsia symptom survey (DSS), nausea severity profile (NSP), and Pediatric Quality of Life Inventory (PedsQL). We grouped patients based on the presence of symptoms prior to COVID-19 test or the test result., Results: One hundred and ninety-six parent(s) or guardian(s) in cohort 1 and 274 in cohort 2 completed surveys and self-reported their child's COVID-19 result. Cohort 1 had increased PEESS and DSS scores, lower PedsQL scores, and increased frequency of abdominal pain disorders among patients with symptoms prior to COVID-19 testing. Both cohorts had increased NP and NSP scores among patients with symptoms prior to COVID-19 testing that was highest among patients with a positive COVID-19 test. Abdominal pain and diarrhea prior to COVID-19 testing predicted higher NP scores., Conclusions: Among symptomatic COVID-19 tested children, we found increased severity of nausea-associated somatic, emotional, and gastrointestinal symptoms in the 3 months following the test that was most increased among patients with a positive COVID-19 test., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Objectives: Chronic nausea and vomiting may be associated with gastroparesis or other conditions. Poor mechanistic understanding of symptoms often precludes targeted therapy. Numerous case series suggest that intrapyloric botulinum toxin injection (IPBI) may be beneficial in treating gastroparesis and dyspepsia in children. We hypothesized that nausea, vomiting, and other symptoms, independent of gastroparesis, may improve with IPBI. We sought to identify gastric emptying (GE) and manometric patterns in IPBI responders versus nonresponders., Methods: Electronic records of 25 pediatric patients who received IPBI for refractory nausea, vomiting, or both were retrospectively reviewed. We assessed symptom improvement post-IPBI and compared symptoms, GE, and antroduodenal manometry (ADM) findings between IPBI responders and nonresponders., Results: At least one major symptom improved in 19 patients (76%) after IPBI. Of 22 patients completing a GE study, 14 had delayed GE with no significant difference between IPBI responders and nonresponders. Of 22 patients who underwent ADM, 18 had normal fasting peristalsis, 5 had postprandial antral hypomotility, 4 had neuropathic findings, and 19 had pylorospasm. IPBI responders, compared to nonresponders, demonstrated higher antral pressures with feeding ( P < 0.0001) and shorter duration of pylorospasm ( P = 0.0036). Antral pressures did not differ significantly with fasting or following motilin agonists., Conclusions: Our findings suggest that IPBI may have therapeutic benefit in pediatric patients with chronic nausea and/or vomiting, independent of gastroparesis. ADM findings of intact antral peristalsis and elevated antral pressures, in conjunction with efficacy of IPBI, support pyloric non-relaxation as a potential contributor to nausea and/or vomiting in pediatric patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning., Methods: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains., Results: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI., Conclusion: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objectives: A high degree of sleep disturbance is reported among youth with disorders of gut-brain interaction (DGBIs). Given that sleep quality impacts a range of pediatric health outcomes including somatic sensations (eg, pain) and depressive mood occurs relatively frequently among youth with DGBIs, there is a dire need to disentangle the unique contributions of sleep and depressive mood on the somatic sensations experienced by youth with DGBIs. We aimed to examine whether depressive mood mediates the relations among sleep disturbance and pain intensity, nausea, and fatigue among youth with DGBIs., Methods: One hundred eighteen patients aged 8-17 years ( Mage = 14.05, SD = 2.88; 70.34% female), 83.05% White/non-Hispanic recruited at a pediatric neurogastroenterology clinic completed measures of sleep disturbance, nausea, fatigue, pain intensity, and depressive mood. Three mediation models examined the effect of sleep disturbance on nausea, fatigue, and pain, with depressive mood as a mediator., Results: Participants reported moderate sleep disturbance. Depressive mood partially mediated the significant, respective relations between greater sleep disturbance and more severe nausea and fatigue. Sleep disturbance was significantly associated with higher pain intensity; however, depressive mood was not a significant mediator of this relation., Conclusions: Sleep quality is a major concern among youth with DGBIs. Low sleep quality may worsen nausea and fatigue via co-occurring increases in depressive mood symptoms. In contrast, sleep disturbance may directly increase pain, regardless of youths' depressive mood symptoms. Future research should explore these relations through prospective studies leveraging a combination of subjective and objective assessment approaches., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders., Methods: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition., Results: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses., Conclusion: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: The aim of the study was to evaluate whether there are clinical subtypes in children with functional nausea based on comorbidities and responses to the Nausea Profile questionnaire., Methods: Patients from the Neurointestinal and Motility Program clinical registry at Lurie Children's Hospital were included if they met Rome IV criteria for functional nausea. Patients completed the Nausea Profile, a multidimensional measure of nausea with gastrointestinal, emotional, and somatic subscales. Comorbidities were assessed by chart review and self-report measures. Latent class analysis was used to identify patient groups based on comorbidities. To assess if model-identified groups were predictive of differences in nausea quality, Nausea Profile subscale means were compared between groups and used to predict group membership. Conversely, k-means analysis was used to divide the sample into groups based upon Nausea Profile subscale scores, to determine if identified groups had different comorbidities., Results: Seventy-two patients (n = 53 girls) with a mean age (±SD) 14.5 ± 2.9 were included. Two clinical subtypes were identified based on comorbidities, with responses on the emotional subscale of the Nausea Profile predicting group membership (P < 0.04). When patients were grouped by nausea quality, the resulting clusters differed on psychiatric comorbidities (P < 0.001)., Conclusions: Our findings support the existence of nausea subtypes within the broad diagnosis of functional nausea. One such subtype is an emotional predominant nausea supporting the notion that anxiety and depression constitute a subset of patients with nausea. Thus, patients may benefit from a treatment approach that integrates both GI assessment and psychiatric support in their care., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Determine whether subjects with chronic nausea and orthostatic intolerance share common alterations in key brain networks associated with central autonomic control: default mode, salience, and central executive networks, and the insula, a key component of the salience network., Methods: Ten subjects (ages 12-18 years; 8 females, 2 males) with nausea predominant dyspepsia, orthostatic intolerance, and abnormal head-upright tilt test were consecutively recruited from pediatric gastroenterology clinic. These subjects were compared with healthy controls (n = 8) without GI symptoms or orthostatic intolerance. Resting-state fMRI and brain network modularity analyses were performed. Differences in the default mode, salience, and central executive networks, and insular connectivity were measured., Key Results: The community structure of the default mode network and salience network was significantly different between tilt-abnormal children and controls (p = 0.034 and 0.012, respectively), whereas, no group difference was observed in the central executive network (p = 0.48). The default mode network was more consistently "intact," and the consistency of the community structure in the salience network was reduced in tilt-abnormal children, especially in the insula., Conclusions and Inferences: Children with chronic nausea and orthostatic intolerance have altered connectivity in the default mode network and salience network/insula, which supports over-monitoring of their body and altered processing of bodily states resulting in interoceptive hyper self-awareness. The connectivity of the salience network would not support optimal regulation of appropriate attention to internal and external stimuli, and the hyper-connected default mode network may result in a persistent self-referential state with feelings of emotion, pain, and anxiety., (© 2021 John Wiley & Sons Ltd.)

Objective: To explore the relationship among gastrointestinal (GI) symptoms, immune response, and autonomic nervous system (ANS) in food protein-induced enterocolitis syndrome (FPIES) in relation to the current understanding of disease phenotype and pathogenesis., Data Sources: Relevant studies related to FPIES, GI symptomatology, and ANS were reviewed. Literature search was performed using PubMed, with keyword combinations including but not limited to FPIES, allergic GI disorders, ANS, autonomic dysfunction, dysautonomia, GI, diarrhea, vomiting, neuroimmune, and clinical phenotyping tools., Study Selections: Peer-reviewed case-control studies, observational studies, reviews and guidelines, and systematic reviews related to FPIES and ANS were selected for review., Results: There is limited research directly relating GI symptoms and FPIES to the ANS and immunologic response. To support the proposed mechanisms of action related to patient symptoms, studies relevant to coexisting GI-autonomic processes and FPIES immunologic triggers were examined. These related disease processes were extrapolated to FPIES based on the current knowledge of FPIES phenotype and pathogenesis., Conclusion: The etiology of FPIES and the underlying mechanisms triggering symptoms are not well understood. On the basis of the exaggerated GI symptoms and hemodynamic response observed, the ANS likely plays an important role in FPIES, possibly as a compensatory response. The trigger for this cascade of symptoms may be related to the disruption of immunologic homeostasis that typically contributes to immune tolerance. To more accurately evaluate FPIES pathophysiology necessitates understanding the diverse spectrum of presenting symptoms. A consistent and comprehensive symptom assessment tool may improve our understanding of this dynamic relationship., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: To detail common comorbidities and procedures performed to evaluate functional nausea in children., Study Design: In total, 63 children age 7-18 years seen in a tertiary care pediatric clinic who met Rome IV criteria for functional nausea prospectively completed an Intake Questionnaire, the Pediatric and Parent-Proxy PROMIS-25 Profile v 2.0, the Pediatric and Parent-Proxy Pediatric Sleep Disturbance-Short Form 4a, and the COMPASS 31 orthostatic intolerance scale to assess comorbidities. Medical records were reviewed for diagnostic tests performed to evaluate nausea and for additional comorbidities. Summary statistics were used to determine the most common comorbidities and diagnostic yield of the procedures. Intraclass correlation coefficients assessed agreement between parent and child reports on the PROMIS scales., Results: Patients with functional nausea experienced multisystem comorbidities. A majority reported abdominal pain, headache, orthostatic intolerance, fatigue, disturbed sleep, anxiety, constipation, allergies, and vomiting. Agreement between parent-proxy and child report of symptoms on PROMIS scales was good to excellent (intraclass correlation coefficients = .78-.83; all P < .001). Patients underwent extensive diagnostic testing: 96 endoscopic procedures, 199 radiologic tests, and 4 cholecystectomies. Most of the procedures were not diagnostically informative., Conclusions: Children with functional nausea have comorbidities outside the gastrointestinal tract that warrant evaluation. Gastrointestinal diagnostic tests were of low-yield in identifying a cause. Understanding the relationship with comorbidities may provide insight into etiologies for the nausea and define clinical phenotypes to better tailor care., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose Diagnostic precision and prolonged testing before, during, and after deglutition is lacking across the age spectrum. Conventional clinical evaluation and radiologic methods are widely used but are reliant on human perception, carrying the risk of subjectivity. High-resolution manometry (HRM) is an emerging clinical and research tool and has the capability to objectively measure the dynamics, kinetics, regulatory, and correlation aspects of deglutition. Method We review the basics of manometry and the methods, metrics, and applications of this technology across the age spectrum. The goal is to aid in the translation of HRM from research tool to clinical use by the speech-language pathologist in the development of better global plans to understand normal and abnormal deglutition. Results HRM is an easily adaptable precise diagnostic tool that can be used to examine deglutition phases and abnormalities across the age spectrum from neonates to nonagenarians and can be a valuable adjunct to specialty evaluation of persistent deglutition disorders. Conclusion New opportunities will emerge upon further research for larger-scale translation once normative data and recognition of biomarkers of abnormality are ascertained.

Background: Due to scarcity of scientific literature on pediatric gastroparesis, there is a need to summarize current evidence and identify areas requiring further research. The aim of this study was to provide an evidence-based review of the available literature on the prevalence, pathogenesis, clinical presentation, diagnosis, treatment, and outcomes of pediatric gastroparesis., Methods: A search of the literature was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines with the following databases: PubMed, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Web of Science. Two independent reviewers screened abstracts for eligibility., Key Results: Our search yielded 1085 original publications, 135 of which met inclusion criteria. Most articles were of retrospective study design. Only 12 randomized controlled trials were identified, all of which were in infants. The prevalence of pediatric gastroparesis is unknown. Gastroparesis may be suspected based on clinical symptoms although these are often non-specific. The 4-hour nuclear scintigraphy scan remains gold standard for diagnosis despite lack of pediatric normative comparison data. Therapeutic approaches include dietary modifications, prokinetic drugs, and postpyloric enteral tube feeds. For refractory cases, intrapyloric botulinum toxin and surgical interventions such as gastric electrical stimulation may be warranted. Most interventions still lack rigorous supportive data., Conclusions: Diagnosis and treatment of pediatric gastroparesis are challenging due to paucity of published evidence. Larger and more rigorous clinical trials are necessary to improve outcomes., (© 2019 John Wiley & Sons Ltd.)

Children with orthostatic intolerance (OI) have exaggerated decreases in heart rate variability (HRV) and suppression of baroreflex sensitivity (BRS) with standing. Accompanying brain transmitter and metabolite profiles are unknown. In this study, we used proton ( 1 H) magnetic resonance spectroscopy ( 1 H-MRS) to quantify markers of neuronal and glial integrity in a pilot study of children with OI compared with asymptomatic controls. Eighteen participants ages 10-18 yr were evaluated for blood pressure, heart rate (HR), and calculated indexes of autonomic function in supine and upright positions and, within an average of 2 wk, underwent 1 H-MRS scans of dorsal medulla on a clinical 3T magnet while supine. As a result, of the 18 participants, 11 tested positive for OI and 7 did not. OI subjects exhibited higher HR and lower HRV and high-frequency α-index (HFα), an index of parasympathetic vagal tone, during standing compared with non-OI. HRV, sequence all (Seq All), high- and low-frequency (HFα and LFα) estimates of the spontaneous BRS decreased significantly, while BP variabilty increased significantly during standing only in subjects with OI. OI subjects had higher myoinositol (mIns) and total choline (tCho), markers of glial inflammation. Upright HFα and Seq All inversely correlated to supine tCho and mIns, respectively, independent of age and sex. In conclusions, in this pilot study, children with OI exhibit higher mIns and tCho in the dorsal medulla while supine that may reflect the well-established impairment in regulation of the autonomic nervous system upon standing. Neuroinflammation as an underlying cause or consequence of autonomic dysfunction is an intriguing possibility requiring further study. NEW & NOTEWORTHY ( 1 H) magnetic resonance spectroscopy detected elevated markers of neuroinflammation in the dorsal medulla in children with impaired autonomic responses to head upright tilt. This first report of altered brain metabolites in this population provides a basis for future clinical studies using this methodology to aide in understanding complex autonomic disease states.

Background: Chronic nausea in pediatrics is a debilitating condition with unclear etiology. We aimed to define hemodynamic and neurohumoral characteristics of chronic nausea associated with orthostatic intolerance in order to improve identification and elucidate mechanism., Methods: Children (10-18 years) meeting Rome III criteria for functional dyspepsia with nausea and symptoms of orthostatic intolerance (OI) completed a Nausea Profile Questionnaire followed by prolonged (45 minutes rather than the traditional 10 minutes) head-upright tilt (HUT) (70° tilt up) test. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured supine and after 15 minutes into HUT. Beat-to-beat heart rate and blood pressure were continuously recorded to calculate their variability and baroreflex sensitivity., Key Results: Within 10 and 45 minutes of HUT, 46% and 85% of subjects, respectively, had an abnormal tilt test (orthostatic hypotension, postural orthostatic tachycardia, or syncope). At 15 and 45 minutes of HUT, nausea was elicited in 42% and 65% of subjects respectively. Higher Nausea Profile Questionnaire scores correlated with positive HUT testing at 10 minutes (P = 0.004) and baroreflex sensitivity at 15 minutes (P ≤ 0.01). Plasma vasopressin rose 33-fold in subjects with HUT-induced nausea compared to twofold in those who did not experience HUT-induced nausea (P < 0.01)., Conclusions and Inferences: In children with chronic nausea and OI, longer duration HUT elicited higher frequency of abnormal tilt testing and orthostatic-induced nausea. The Nausea Profile Questionnaire predicted the orthostatic response to tilt testing. Exaggerated vasopressin release differentiated patients with HUT-induced nausea (vs those without nausea), suggesting a possible mechanism for chronic nausea in childhood., (© 2018 John Wiley & Sons Ltd.)

Objective: To improve understanding of the interrelatedness of airway and esophageal diagnoses by evaluating the yield of procedural and radiographic testing of the gastrointestinal tract in children with airway conditions by their referring diagnoses in a pediatric aerodigestive clinic., Methods: A retrospective chart review of all 325 patients seen in the aerodigestive program from 2010 to 2013 was performed in a single academic medical center. Demographics and results from esophagogastroduodenoscopies with biopsies (EGD), upper gastrointestinal fluoroscopy studies (UGI), and pH multichannel intraluminal impedance probe (pH-MII) performed within 30 days of the clinic visit were evaluated according to presenting diagnoses., Results: Mean patient age was 3.15 years (range 0.15-24 years) and 41.2% were born premature. 189/325 (58.1%) were on acid suppression. A total of 295 EGD, 193 pH-MII, and 54 UGI were performed. The most common diagnosis with an abnormal pH-MII was asthma. The most common diagnoses with an abnormal EGD were feeding difficulty and tracheal esophageal fistula/ esophageal atresia (TEF/EA). EGDs were normal in 188/295 (63.7%), while 39/295 (13.2%) demonstrated esophagitis, and 22/295 (7.5%) had >15 esophageal eosinophils per high power field. The majority of pH-MII (144/193 [74.6%]) and UGI (47/54 [87%]) were normal., Conclusions: Children with feeding difficulty, TEF/EA, and asthma were the mostly likely to have a histologic abnormality on EGD or an abnormal pH-MII. The majority of children were previously prescribed acid suppression medication and had a referring diagnosis of gastroesophageal reflux disease but were subsequently found to have normal evaluation. Prospective studies are needed to optimize care of this population., (© 2018 Wiley Periodicals, Inc.)

Orthostatic intolerance (OI), having difficulty tolerating an upright posture because of symptoms or signs that abate when returned to supine, is common in pediatrics. For example, ∼40% of people faint during their lives, half of whom faint during adolescence, and the peak age for first faint is 15 years. Because of this, we describe the most common forms of OI in pediatrics and distinguish between chronic and acute OI. These common forms of OI include initial orthostatic hypotension (which is a frequently seen benign condition in youngsters), true orthostatic hypotension (both neurogenic and nonneurogenic), vasovagal syncope, and postural tachycardia syndrome. We also describe the influences of chronic bed rest and rapid weight loss as aggravating factors and causes of OI. Presenting signs and symptoms are discussed as well as patient evaluation and testing modalities. Putative causes of OI, such as gravitational and exercise deconditioning, immune-mediated disease, mast cell activation, and central hypovolemia, are described as well as frequent comorbidities, such as joint hypermobility, anxiety, and gastrointestinal issues. The medical management of OI is considered, which includes both nonpharmacologic and pharmacologic approaches. Finally, we discuss the prognosis and long-term implications of OI and indicate future directions for research and patient management., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Boris has served as a paid expert witness on the subject of postural orthostatic tachycardia syndrome. H. Lundbeck A/S (which underwrote a meeting of the Pediatric Subgroup of the American Autonomic Society) produces Northera (droxidopa) to treat orthostatic intolerance as well as citalopram and escitalopram; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Pepsin in saliva is a proposed biomarker for oropharyngeal reflux. Pepsin may be prevalent in saliva from subjects with gastro-esophageal reflux and may correlate with proximal reflux by intraluminal impedance/pH monitoring (MII/pH)., Methods: Patients (3 days to 17.6 years, n=90) undergoing 24-hour MII/pH monitoring and asymptomatic controls (2 months to 13.7 years, n=43) were included. Salivary pepsin was determined using a pepsin enzyme-linked immunosorbent assay. Eight saliva samples were collected from patients undergoing 24-hr MII/pH: (i) before catheter placement, (ii) before and 30 minutes after each of three meals, and (iii) upon awakening. One sample was collected from each control., Key Results: In MII/pH subjects, 85.6% (77/90) had at least one pepsin-positive sample compared with 9.3% (4/43) in controls. The range of pepsin observed in individual subjects varied widely over 24 hours. The average pepsin concentration in all samples obtained within 2 hours following the most recent reflux event was 30.7±135 ng/mL, decreasing to 16.5±39.1 ng/mL in samples collected more than 2 hours later. The frequency of pepsin-positive samples correlated significantly with symptom index (r S =0.332, P=.0014), proximal (r S =0.340, P=.0010), and distal (r S =0.272, P=.0095) MII events., Conclusions & Inferences: Concentration of salivary pepsin may not be an accurate measure of severity of reflux because of the wide range observed in individuals over 24 hours. Saliva samples must be obtained soon after a reflux event. Defining a regimen for optimal saliva collection may help to achieve the goal of using salivary pepsin as a biomarker for oropharyngeal reflux., Clinical Trial Registry: NCT01091805., (© 2016 John Wiley & Sons Ltd.)

This study compared anxiety and physiological responses during the Trier Social Stress Test for Children (TSST-C) in adolescents. 38 subjects (26 females) were enrolled: 11 cyclic vomiting syndrome (CVS), 11 anxiety, and 16 controls. Salivary cortisol, α-amylase and heart rate variability (HRV) were assessed during the TSST-C. Anxiety was measured by the Screen for Childhood Anxiety Related Emotional Disorders (SCARED), Anxiety Disorders Interview Schedule, and State-Trait Anxiety Inventory for Children (STAI-C). 11 anxiety and 7 CVS subjects had ≥1 anxiety disorder. 82% in the anxiety and CVS groups met criteria for an anxiety disorder on the SCARED. Combining groups, cortisol increased from baseline to recovery during the TSST-C (p=0.0004) and the stressor to recovery (p=0.005). α-amylase did not differ during the TSST-C for the total sample, but increased for anxiety compared to controls from baseline to recovery (p=0.01). HRV decreased during the stressor (p=0.0001) and increased at recovery (p=0.004). No associations were found between biomarkers and trait anxiety. Associations were found between baseline HRV and pre-test state anxiety (r=-0.406, p=0.012) and between recovery HRV and post-test state anxiety (r=-0.501, p=0.002) for the total sample. Anxiety is prevalent in CVS warranting screening. HRV may serve as a biomarker for evaluating stress as a potential trigger for CVS episodes. State but not trait anxiety was associated with changes in HRV, suggesting acute anxiety may be more relevant in linking stress and CVS episodes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Determine clinical and manometric parameters associated with success of antegrade continence enemas (ACEs) administered via cecostomy in the treatment of constipation and fecal overflow incontinence., Methods: We performed a retrospective review of clinical symptoms and manometry (colonic and anorectal) before cecostomy in 40 pediatric patients (20 males, 20 females). The mean age at time of follow-up was 9.5 ± 4.4 years with a mean follow-up time of 12.2 ± 10.9 months. Clinical outcomes were defined as good, if subjects had >3 bowel movements per week, <2 episodes of soiling per week, and absence of pain at the time of follow-up after cecostomy., Results: Before cecostomy, the mean duration of constipation and/or fecal incontinence was 7.7 ± 4.4 years, mean number of BMs was 1.5 ± 0.9 per week, and soiling episodes 4.12 ± 3.5 per week; 24 (60%) patients had abdominal pain. At follow-up 30 out of 40 patients had a good outcome, and 10 had a poor outcome; with a difference in the number of weekly BM of 5.7 ± 2.2 versus 1.5 ± 0.9, P < 0.001, and soiling episodes (0.4 ± 1.5 vs 4 ± 3.1, P < 0.001). There was no difference in the duration of symptoms between groups. Obesity was more common in the poor-outcome group, 60% versus 21% (P = 0.01). Abdominal pain was more common in the poor-outcome group, 100% versus 47% (P = 0.003). Normal colonic manometry was associated with good outcome, whereas absence of high-amplitude propagating contraction (HAPC) in any part of the colon was associated with poor outcome. No other differences in colonic manometry were observed between the good- and poor-outcome groups with the exception of a trend toward decreased number of sigmoid HAPCs in the poor-outcome group (P = 0.07). No differences were observed in anorectal manometry measurements between good- and poor-outcome groups with the exception of an observable increased baseline resting pressure in the poor outcome (P = 0.05)., Conclusions: Obesity and abdominal pain tend to be associated with poor outcomes after cecostomy for refractory constipation. Normal colonic and anorectal manometry were associated with good outcome. Absence of HAPC in any part of the colon, and increased baseline resting pressure of the anal canal were more associated with poor outcome. No other specific differences in either colonic or anorectal manometric parameters were observed in patients with good versus poor outcomes with cecostomy. Large prospective studies potentially combining other diagnostic modalities such as colonic transit studies are needed to determine the optimal tests to predict successful outcomes from cecostomy.

Objectives: Endoscopic ultrasound (EUS) ± fine needle aspiration (FNA) is a useful tool to evaluate gastrointestinal tract disorders in adults because of its established feasibility and safety. Its role in children has not been well established and continues to evolve. Our objective was to evaluate the utility and impact on clinical management of EUS and EUS-guided interventions in the pediatric population at our institution., Methods: Retrospective, single-center study including 43 patients undergoing EUS and EUS-FNA between August 2005 and January 2012., Results: Fifty-one EUS procedures were performed in 43 patients, 30 girls, median age 14.5 (range 4-18). The most common indications were suspected biliary obstruction in 11 of 51 (22%), pancreatic cysts in 10 of 51 (20%), acute or recurrent pancreatitis in 9 of 51 (18%), and abdominal pain in 8 of 51 (16%). The most common findings of EUS included normal 11 of 51 (22%), pancreas cyst 6 of 51 (12%), pancreatic pseudocyst 5 of 51 (10%), biliary system sludge or stones 9 of 51 (18%), and acute and chronic pancreatitis 5 of 51 (10%). EUS-FNA was performed in 13 cases: 7 solid masses or nodes, 4 pancreatic pseudocyst, 1 pancreatic cyst, and 1 celiac plexus block. FNA cyst drainage was successful in resolving all 4 pancreatic pseudocysts. EUS prompted a surgical procedure in 13 cases (25%), ERCP in 5 cases (10%), and repeat EUS in 5 cases (10%). EUS led to a new diagnosis in 34 of 43 (79%) patients and prompted further intervention in 24 of 51 (47%) procedures., Conclusions: In this large cohort study, we found that EUS and EUS-guided interventions assist in diagnosing and altering clinical management in pediatric patients and should be considered in cases with vexing pancreaticobiliary disorders.

Autonomic dysregulation and heterogeneous symptoms characterize postural orthostatic tachycardia syndrome (POTS). This study evaluated the effect of high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM(®)), a noninvasive, allostatic neurotechnology for relaxation and auto-calibration of neural oscillations, on heart rate variability, brain asymmetry, and autonomic symptoms, in adolescents with POTS. Seven subjects with POTS (three males, ages 15-18) underwent a median of 14 (10-16) HIRREM sessions over 13 (8-17) days. Autonomic function was assessed from 10-min continuous heart rate and blood pressure recordings, pre- and post-HIRREM. One-minute epochs of temporal high-frequency (23-36 Hz) brain electrical activity data (T3 and T4, eyes closed) were analyzed from baseline HIRREM assessment and subsequent sessions. Subjects rated autonomic symptoms before and after HIRREM. Four of seven were on fludrocortisone, which was stopped before or during their sessions. Heart rate variability in the time domain (standard deviation of the beat-to-beat interval) increased post-HIRREM (mean increase 51%, range 10-143, p = 0.03), as did baroreflex sensitivity (mean increase in high-frequency alpha 65%, range -6 to 180, p = 0.05). Baseline temporal electrical asymmetry negatively correlated with change in asymmetry from assessment to the final HIRREM session (p = 0.01). Summed high-frequency amplitudes at left and right temporal lobes decreased a median of 3.8 μV (p = 0.02). There was a trend for improvements in self-reported symptoms related to the autonomic nervous system. Use of HIRREM was associated with reduced sympathetic bias in autonomic cardiovascular regulation, greater symmetry and reduced amplitudes in temporal lobe high-frequency electrical activity, and a trend for reduced autonomic symptoms. Data suggest the potential for allostatic neurotechnology to facilitate increased flexibility in autonomic cardiovascular regulation, possibly through more balanced activity at regions of the neocortex responsible for autonomic management. Clinical trial registry "Tilt Table with Suspected postural orthostatic tachycardia syndrome (POTS) Subjects," Protocol Record: WFUBAHA01.

Studies of adults with orthostatic intolerance (OI) have revealed altered neurohumoral responses to orthostasis, which provide mechanistic insights into the dysregulation of blood pressure control. Similar studies in children with OI providing a thorough neurohumoral profile are lacking. The objective of the present study was to determine the cardiovascular and neurohumoral profile in adolescent subjects presenting with OI. Subjects at 10-18 yr of age were prospectively recruited if they exhibited two or more traditional OI symptoms and were referred for head-up tilt (HUT) testing. Circulating catecholamines, vasopressin, aldosterone, renin, and angiotensins were measured in the supine position and after 15 min of 70° tilt. Heart rate and blood pressure were continuously measured. Of the 48 patients, 30 patients had an abnormal tilt. Subjects with an abnormal tilt had lower systolic, diastolic, and mean arterial blood pressures during tilt, significantly higher levels of vasopressin during HUT, and relatively higher catecholamines and ANG II during HUT than subjects with a normal tilt. Distinct neurohumoral profiles were observed when OI subjects were placed into the following groups defined by the hemodynamic response: postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), syncope, and POTS/syncope. Key characteristics included higher HUT-induced norepinephrine in POTS subjects, higher vasopressin in OH and syncope subjects, and higher supine and HUT aldosterone in OH subjects. In conclusion, children with OI and an abnormal response to tilt exhibit distinct neurohumoral profiles associated with the type of the hemodynamic response during orthostatic challenge. Elevated arginine vasopressin levels in syncope and OH groups are likely an exaggerated response to decreased blood flow not compensated by higher norepinephrine levels, as observed in POTS subjects. These different compensatory mechanisms support the role of measuring neurohumoral profiles toward the goal of selecting more focused and mechanistic-based treatment options for pediatric patients with OI., (Copyright © 2016 the American Physiological Society.)

This study evaluated the relationship among nausea, anxiety, and orthostatic symptoms in pediatric patients with chronic unexplained nausea. We enrolled 48 patients (36 females) aged 15 ± 2 years. Patients completed the Nausea Profile, State-Trait Anxiety Inventory for Children and underwent 70° head upright tilt testing (HUT) to assess for orthostatic intolerance (OI) and measure heart rate variability (HRV). We found nausea to be significantly associated with trait anxiety, including total nausea score (r = 0.71, p < 0.01) and 3 subscales: somatic (r = 0.64, p < 0.01), gastrointestinal (r = 0.48, p = 0.01), and emotional (r = 0.74, p < 0.01). Nausea was positively associated with state anxiety, total nausea (r = 0.55, p < 0.01), somatic (r = 0.48, p < .01), gastrointestinal (r = .30, p < .05), and emotional (r = .64, p < .01) subscales. Within 10 min of HUT, 27 patients tested normal and 21 demonstrated OI. After 45 min of HUT, only 13 patients (27%) remained normal. Nausea reported on the Nausea Profile before HUT was associated with OI measured at 10 min of tilt (nausea total r = 0.35, p < 0.05; nausea emotional subscale r = 0.40, p < 0.01) and lower HRV at 10 min of HUT (F = 6.39, p = 0.01). We conclude that nausea is associated with both anxiety symptoms and OI. The finding of decreased HRV suggests an underlying problem in autonomic nervous system function in children and adolescents with chronic unexplained nausea.

Background: We hypothesized that orthostatic intolerance (OI) is associated with gastric dysrhythmias, nausea, and abdominal pain, which improves using fludrocortisone to treat OI., Methods: Patients (n=16, girls) with OI completed questionnaires before and after fludrocortisone treatment (age 14.8 ± 2.8 years). Ten patients underwent electrogastrograms (EGGs) before fludrocortisone., Results: All EGGs showed gastric dysrhythmias. Fludrocortisone reduced mean scores as follows: nausea, 3.1 ± 0.8 to 2.1 ± 1.1 (P=0.016); dizziness, 3.0 ± 1.0 to 2.2 ± 1.1 (P=0.0371); abdominal pain, 2.8 ± 1.3 to 1.9 ± 1.4 (P=0.0063); flushing, 2.3 ± 1.2 to 1.5 ± 1.4 (P=0.0476); and missing school, 2.2 ± 1.5 to 1.2 ± 1.5 (P=0.0078)., Conclusions: Chronic nausea and abdominal pain accompany OI and improve with OI treatment.

Objective: Gastrointestinal disturbances as a result of changes in eating patterns have been described in eating disorders. Many patients who experience irritable bowel syndrome report changes in eating patterns as a way to cope with their symptoms. Little is known about the consequences of these practices. The aim of this study was to explore whether repeated eating restriction (defined as not eating ≥ 4 hours while hungry) is associated with motility disturbances., Methods: Of 17 patients with irritable bowel syndrome, subjects were divided into those who habitually restrict their eating (n = 8) and those without eating restriction (n = 9) (age range 15-21, mean 19.2; 64.7% girls). Whole-gut transit time was measured by radiopaque markers, gastric sensitivity was measured by water load test (drinking max of 800 mL of water in 5 minutes or until full), and gastric dysrhythmias by an electrogastrogram., Results: Restrictors drank less water (mean 464.4 mL) than nonrestrictors (mean 613 mL; P = 0.02). No difference was found in gastric dysrhythmias (62.5% vs 77.8%; P = 0.5). Whole-gut transit tended to be slower in the restrictors (mean 51.0 hours) than in nonrestrictors (mean 37.5 hours), but this was not significant., Conclusions: Eating restriction appears to be associated with increased gastric sensation. More data are needed from larger studies to determine whether eating behaviors are associated with other motility disturbances.

The digestive tract is designed for the optimal processing of food that nourishes all organ systems. The esophagus, stomach, small bowel, and colon are sophisticated neuromuscular tubes with specialized sphincters that transport ingested food-stuffs from one region to another. Peristaltic contractions move ingested solids and liquids from the esophagus into the stomach; the stomach mixes the ingested nutrients into chyme and empties chyme from the stomach into the duodenum. The to-and-fro movement of the small bowel maximizes absorption of fat, protein, and carbohydrates. Peristaltic contractions are necessary for colon function and defecation.

Unlabelled: INTRODUCTION/RESULTS: In 17 patients, chronic idiopathic nausea was associated with orthostatic intolerance (OI) by abnormal tilt table tests (88%) or gastric dysrhythmias (71%). After fludrocortisone treatment, there was >26% nausea improvement in 71%, 1-25% in 6%, and no improvement in 24%. In six subjects, EGGs repeated after >50% nausea improvement all remained to be abnormal, suggesting nausea is independent of gastric dysrhythmias., Conclusion: Association of EGG abnormalities and OI in this subset of nausea patients suggests a generalized disturbance of autonomic regulation.

Percutaneous endoscopic gastrostomy (PEG) is a relatively safe and minimally invasive surgical method for providing enteral access in children. In pediatrics, the indications for PEG placement frequently include malnutrition or failure to thrive, as well as oropharyngeal dysphagia, especially in children with neurological impairment (NI). The risk for postoperative complications is low. However, among children with NI, gastroesophageal reflux disease (GERD) may necessitate fundoplication prior to gastrostomy tube placement. Preoperative pH probe testing has not been shown to be an effective screening tool prior to PEG placement among patients with GERD. Laparoscopic gastrostomy tube insertion was introduced in pediatric patients in an attempt to decrease complications associated with PEG. Although outcomes were reported to be similar to or better than PEG alone, future comparative studies are needed to better define the optimal patient demographic for this technique., (© Springer Science+Business Media, LLC 2011)

Purpose: Biliary microlithiasis is an uncommon but recognized cause of upper abdominal pain, cholecystitis, cholangitis, and pancreatitis in adults. Gallstones smaller than 3 mm may not be seen on transabdominal ultrasound and may only be seen on endoscopic ultrasound. This condition is poorly described in children. The aim of this study is to review the results of laparoscopic cholecystectomy to treat biliary microlithiasis in a pediatric case series., Methods: We performed a retrospective case review of children with biliary microlithiasis who were treated with laparoscopic cholecystectomy., Results: Three children were diagnosed with biliary microlithiasis. Two patients had recurrent right upper quadrant pain and nausea. A third patient had midepigastric pain and idiopathic pancreatitis. All 3 had a normal gallbladder on transabdominal ultrasound. Additional imaging with hepatobiliary scan, computed tomography, and magnetic resonance cholangiopancreatography revealed no biliary source for symptoms. Endoscopic ultrasound was performed on all 3 children, demonstrating microlithiasis of the gallbladder. Each child had a laparoscopic cholecystectomy with intraoperative cholangiogram. No abnormalities were seen on intraoperative cholangiogram. All 3 children had alleviation of pain and improvement of symptoms in postoperative follow-up., Conclusion: Children with biliary microlithiasis and associated clinical symptoms can be successfully treated with laparoscopic cholecystectomy. Endoscopic ultrasound should be considered in the evaluation of the child with clinical biliary symptoms and a negative transabdominal ultrasound result., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: A gastro-jejunal (G-J) feeding tube is a safe and useful temporizing method of providing enteral access in children. Although G-J tubes are often used to obviate the need for a surgical jejunostomy, their long-term use is often associated with mechanical failure., Aim: To review the clinically effective durability of G-J feeding tubes in providing enteral access in children., Methods: We performed a retrospective review of 102 patients at the Johns Hopkins Children's Center from 1994-2003 whose underlying diagnosis necessitated the need for postpyloric enteral access., Results: Long-term follow-up was obtained in 85 (48 M; 37 F) patients with a median (range) age of 2.0 (0.1-18.0) yr. The most common indication for G-J tube placement was gastroesophageal reflux with aspiration in 51 patients and feeding intolerance and vomiting in 19 patients. The mean (range) number of tube replacements was 2.2 (1-14) over a median (range) duration of follow-up of 39 (2-474) days. The indication for G-J tube replacement included: tube displacement (58), a clogged tube (41), and a cracked tube or ruptured balloon (35). In 52 cases, the cause for G-J tube replacement was undetermined., Conclusions: G-J feeding tubes are associated with the frequent need for tube maintenance and replacement and may not be the most feasible clinical option in providing long-term (>1 month) enteral access in children intolerant to gastrostomy tube feeds. Future studies are needed to develop innovative percutaneous jejunostomy tube placement techniques that facilitate long-term enteral access.

Background: Elevated awake resting heart rate (HR) has been shown to be a major risk factor for cardiovascular disease. Since coronary ischaemic events appear to peak during transition from sleep to awake HR, we sought to determine whether the degree of diurnal HR fluctuation (dHRV) is an independent predictor of coronary and peripheral atherogenesis. In this study, we varied both baseline HR and dHRV using sino-atrial node ablation (SNA) in a primate model of diet-induced atherogenesis and determined the degree of plaque formation relative to both HR parameters., Methods: HR was recorded continuously for 6 months by an implantable intraaortic sensor/transmitter in 17 active unrestricted male cynomolgus monkeys. In nine monkeys, SNA was employed to create a wide spectrum of dHRV, and the power amplitude of dHRV was determined for the daily HRV cycle with power spectral analysis. After a 6-month diet induction period, percent coronary and carotid stenosis, intimal thickness and area were quantitated in each animal., Results: Total serum cholesterol and mean HR were no different between high ( n= 10) and low ( n= 7) dHRV groups (866 mg% vs. 740 mg%, P> 0.2 and 130 +/- 22 and 115 +/- 13, P> 0.1, respectively). Percent carotid stenosis was markedly greater in both high HR and dHRV animals ([HR], 54 +/- 19 vs. 35 +/- 10, P< 0.04) and ([dHRV], 54 +/- 17 vs. 32 +/- 10, P< 0.01). Significant increases in all measures of coronary atherogenesis were found in high dHRV animals when compared with those with low dHRV (percent stenosis: 48% +/- 22 vs. 23% +/- 16, P< 0.02), (lesion area: 1.2 +/- 0.8 vs. 0.3 +/- 0.3, P< 0.02), and (intimal thickness: 0.3 +/- 0.1 vs. 0.1 +/- 0.1, P< 0.01), respectively. While there was a trend towards greater coronary atherogenesis in animals with high HR, this did not reach statistical significance., Conclusion: Elevated HR and dHRV are both associated with enhanced experimental atherosclerotic plaque formation. However, a greater degree of carotid and coronary atherogenesis is observed in animals with high dHRV. These findings suggest that elevated dHRV is a stronger predictor for susceptibility to atherogenesis than elevated HR alone. Such a relationship may be attributed to the potential role of dHRV in modulating the frequency of adverse near wall haemodynamic forces, which have been shown to induce atherosclerotic plaques. Lowering of dHRV in humans by exercise or pharmacological agents may have a beneficial role in retarding atherosclerotic plaque induction, progression and complication.

Purpose: An elevated plasma level of lipoprotein (a) is an independent risk factor for atherothrombotic cardiovascular disease by yet undefined mechanisms. We have previously reported that matrix metalloproteinases cleave apolipoprotein (a) into 2 main fragments, F1 and F2, the latter (the C-terminal domain) exhibiting in vitro a high-affinity binding to extracellular matrix components, including fibrin(ogen). We therefore tested the hypothesis that the lipoprotein (a) matrix metalloproteinase-derived F2 is localized in potentially or morphologically unstable human carotid plaque at regions of increased matrix metalloproteinase activity., Methods: Carotid plaques removed after endarterectomy (n = 18) were evaluated for structural features indicative of instability (thin fibrous cap, inflammation, and proximity of the necrotic core to the lumen); each plaque was classified as unstable (n = 10) or stable (n = 8). Western blot analysis was performed to quantitate apolipoprotein (a) and its fragments F1 and F2 in plaque extracts. Immunohistochemical staining was used to localize apolipoprotein (a) and its fragments within the atherosclerotic plaque. In situ zymography was used to determine regions of gelatinase (matrix metalloproteinase 2 and matrix metalloproteinase 9) activity., Results: Western blot analyses demonstrated a 2.5-fold higher density of F2 in unstable plaques than in stable plaques (3.07 +/- 1.9 vs 1.18 +/- 0.8; P <.05). In morphologically unstable plaques, there was preferential distribution of F2 within regions of fibrous cap inflammation and/or foam cell accumulation and within abluminal necrotic cores. In morphologically stable plaques, however, localization was predominantly found in the medial smooth muscle cells. Regions of enhanced matrix metalloproteinase 2 and matrix metalloproteinase 9 activity co-localized with the transmural distribution of F2 within the plaque., Conclusions: These findings suggest that F2 in regions of increased matrix metalloproteinase activity is a potential mechanism for superimposed thrombotic events in morphologically unstable human carotid plaques. The relationship between plasma lipoprotein (a) levels and accumulation of F2 and the potential correlation of F2 to human plaque disruption and thrombosis warrant further study.

Background: Although ionizing radiation (IR) has been demonstrated to attenuate vessel wall restenosis and intimal hyperplasia (IH), dose-related mural injury and atrophy are possible deleterious side effects. We tested the hypothesis that a radiosensitizing strategy may improve IR-induced inhibition of in vivo vascular smooth muscle cells (VSMCs) without influencing apoptotic cell death., Methods: In 28 New Zealand White rabbits, the right common carotid artery (CCA) was injured and subjected to low-flow conditions to promote IH. The CCA was transfected with an adenoviral vector incorporating the cytosine deaminase (CD) gene (1 x 10(9) PFU/ml). 5-Fluorocytosine (5-FC), a prodrug that is converted to the radiosensitizing agent 5-fluorouracil (5-FU) by CD, was thereafter administered intravenously. The CCA was exposed to 5 Gy IR at 24 h. Intimal/medial (I/M) area and thickness ratios were determined in the harvested CCAs at 14 days. VSMC proliferative and apoptotic indices were assessed with immunohistochemistry., Results: A 50% reduction in I/M area was found in rabbits treated with IR and IR + CD/5-FC (0.19 +/- 0.03 and 0.18 +/- 0.02) when compared with untreated controls (UC) (0.37 +/- 0.06) (P = 0.005). This finding was substantiated by attenuation of I/M thickness in the IR groups [0.47 +/- 0.13 (IR), 0.41 +/- 0.11 (IR + CD/5-FC), 0.61 +/- 0.17 (UC)] (P = 0.007). The number of proliferating VSMCs was notably smaller when IR was combined with CD/5-FC (4.17 +/- 1.16 vs 2.97 +/- 1.09 log transformed cells/mm(2), P < 0.07). Apoptosis was similar in all groups., Conclusions: Both IR alone and IR combined with a radiosensitizing agent are effective in attenuating experimental IH. However, combination therapy is synergistic and achieves greater inhibition of VSMC proliferation and may involve selective killing of radioresistant S-phase VSMCs. IR + CD/5-FC represents a novel therapeutic strategy that offers potential for long-term control of IH., (Copyright 2000 Academic Press.)

We have previously demonstrated that high-flow (HF) conditions inhibit experimental intimal hyperplasia. We hypothesized that such flow conditions may alter transforming growth factor-beta1 (TGF-beta1) after mural injury. The right common carotid artery (CCA) was balloon-injured in 54 New Zealand White male rabbits. Flow was thereafter preserved (normal flow [NF]), reduced by partial outflow occlusion (low flow [LF]), or increased by ligation of the left CCA (HF). Four sham-operated animals served as uninjured controls. Mean blood flow and pressure in the right CCA were measured before and after flow modulation and before euthanasia (3, 7, and 14 days). TGF-beta1 mRNA and protein levels in the right CCA were determined by Northern and ELISA analyses at each time point. At 7 and 14 days, intimal hyperplasia was quantified, and the transmural localization of TGF-beta1 was determined by immunohistochemical analysis. Mean flow was reduced from 22+/-1 to 10+/-3 mL/min in the LF group and increased to 34+/-2 mL/min in the HF group (P<0.001). Blood pressure was not different among the flow groups for all time points. Wall shear stress was markedly decreased in the LF group to 14+/-4 dyne/cm(2) and increased in the HF group to 63+/-6 dyne/cm(2) at 7 days compared with values in uninjured controls (39+/-2 dyne/cm(2), P<0.001) and the NF group (44+/-7 dyne/cm(2), P<0.001). At 14 days, wall shear stress was similar among the flow groups. The intima-to-media ratio was 5- and 2-fold greater in the LF group than in the HF and NF groups at 14 days. mRNA levels for TGF-beta1 and its active ligand were increased in the HF group by at least 2- and 3-fold, respectively, at 3 and 7 days compared with levels in uninjured controls and the LF group (P<0.05) but were not different among the flow groups at 14 days. TGF-beta1 preferentially localized in the abluminal vascular smooth muscle cells of the HF arterial segments. Flow- and shear-mediated release of TGF-beta1 may therefore play a role in abrogating the proliferative and migratory response of vascular smooth muscle cells in the early stages after mural injury.

Biomechanical forces have been implicated in the induction and progression of intimal hyperplastic thickening in vein, prosthetic, and endovascular bypass grafts. Graft implantation imposes significant alterations is shear and tensile forces. Such physical forces play an important role in modulating those cellular and molecular events that underlie regulation of vascular healing and adaptation. Characterization of such hemodynamic variables that induce perpetual medial vascular smooth muscle cell proliferation and migration will help in identification of those grafts at risk for occlusion and limited long-term patency and in design of therapeutic strategies that attenuate progressive intimal hyperplasia.

Intimal hyperplasia represents a serious complication limiting the long-term benefits of vascular interventions such as balloon angioplasty and stent placement. Although pharmacological interventions have attempted to curtail restenosis, they have not been shown to be effective to date. Radiotherapy is one alternative that has shown promise as an inhibitor of intimal hyperplasia in several animal models. Irradiation causes cell death by producing irreparable damage to DNA. This is believed to be the mechanism of inhibition of VSMC proliferation. Delivery of irradiation can be either intraluminal via an angiographically directed catheter or extraluminal using an external radiation source such as an x-ray device. Intraluminal irradiation has generally utilized either gamma or beta-emitting sources. Both have been effective in producing a dose response, although some studies advocate the use of beta-type irradiation as a safer, more efficient means of delivery. Extraluminal irradiation also has been an effective inhibitor of intimal hyperplasia. Studies suggest that this form of irradiation provides a more even-dose distribution to vessel walls than an intravascular delivery system. The use of radiotherapy has more recently been extended to clinical trials, and initial studies have shown promising results. The success of irradiation must be balanced with its potential complications including radiation-induced arteritis, coronary artery stenosis, and secondary development of malignancy. Although these have been associated with irradiation, the dose used in these cases was often considerably higher than those used in the treatment of intimal hyperplasia. Finally, with the advent of gene therapy, irradiation may provide an additional means of supplementing this new type of therapy through radiation-inducible gene therapy.

Purpose: The purpose of this study was to determine factors that may influence patient selection for surgery in recurrent carotid stenosis (RCS) and to contrast the results of primary and secondary carotid endarterectomy (CENDX) with regard to operative morbidity and stroke prevention., Methods: Forty-eight patients who underwent CENDX for RCS (RCS-OP group) were compared with a contemporaneous group of 40 patients who on at least one post-CENDX duplex ultrasonography study had a greater than 50% stenosis but did not undergo operation (RCS-NO-OP group). This latter group was drawn from 1053 follow-up duplex studies in 348 patients who underwent primary CENDX between the years 1983 and 1993. Each of these two groups was compared with a metanalysis of six key series derived from the literature., Results: No significant differences were seen in the demographics or the incidence of risk factors between the two groups except for a higher incidence of coronary artery disease (p < 0.03) and peripheral vascular disease (p < 0.001) in the RCS-OP group. The operation-specific stroke rate was 2.1%, and the 30-day mortality was also 2.1%. Symptomatic RCS was the indication in 56% of cases. Important anatomic differences were found between groups. The duplex/arteriographic degree of stenosis was greater than 90% in 75% of the patients in the RCS-OP group, whereas only 10% of the patients in the RCS-NO-OP group had greater than 80% stenosis, most being in the 50% to 80% range. An unexpected finding was the sudden progression to occlusion in 10 (25%) of 40 in the RCS-NO-OP group, with 2 (5%) of 10 of the occlusions presenting as unheralded strokes. Overall, a stroke without an antecedent transient ischemic attack occurred in 3 (7.5%) of 40 of patients in the RCS-NO-OP group, all in patients with greater than 75% stenosis on their last documented scan preceding the stroke., Conclusion: Given the relatively low stroke rate with surgery in the RCS-OP group (2.1%) and the higher incidence of unheralded strokes (7.5%) in the RCS-NO-OP group, a more aggressive approach may be warranted in patients with asymptomatic high-grade (> 75%) RCS, a strategy not unlike that adopted for primary CENDX.

Human lymphoblastoid cell lines derived from WI-L2 exhibit unexpected frequencies of diaminopurine (DAP) resistant mutants. The background mutant fractions of 10(-7) to 10(-8) in untreated cultures are much lower than the frequencies expected for loss of a heterozygous autosomal locus (10(-5) to 10(-6), yet much higher than expected for a homozygous locus (10(-10) to 10(-12). We used aminopterin, adenine and thymidine (AAT) to select DAP-sensitive (DAPS) revertants from one resistant line. The background frequency of DAPR in these revertant cell lines ranged from 3.5 to 6.5 x 10(-4), approximately the square root of 10(-7). Thus these data suggest that both alleles of aprt are inactivated at similarly high frequencies. They also indicate that the DAPS revertants were heterozygotes (aprt +/-) or hemizygotes (aprt +/0) and that WI-L2 was homozygous (aprt+/+). Mutational dose-response studies with X-rays, ethyl methanesulfonate (EMS), and ICR-191 were conducted in 4 of these revertant cell lines. EMS and ICR-191, which induce mainly point mutations, did not induce an increase in mutant fraction. A dose of 200 cGy X-rays, however, induced a frequency of 10(-3). Treatment of DAPR cells with 5-azacytidine induced a significant increase in reversion to DAPS. Southern blot analysis of the aprt gene after digestion with MspI or HpaII also suggests that differential methylation changes may play a major role in the generation of DAP sensitivity and resistance.